Key result
Olmesartan pretreatment dose-dependently decreased mechanical strain-induced p-ERK plateau levels in rat mesangial cells (maximal inhibition 50.6 +/- 11.0% at 10^-5 M).
Why the study?
Does olmesartan reduce mechanical strain-induced ERK phosphorylation and oxidative stress in rat mesangial cells in the absence of Angiotensin II?
Does olmesartan reduce mechanical strain-induced ERK phosphorylation and oxidative stress in rat mesangial cells in the absence of Angiotensin II?
Olmesartan attenuates mechanical strain-induced ERK phosphorylation and oxidative stress in mesangial cells independently of Angiotensin II, highlighting its inverse agonistic activity.
Suggests inverse agonism of olmesartan on strain-induced ERK in mesangial cells; hypothesis-generating and requires human validation before clinical consideration.
It has been reported that mechanical strain activates extracellular signal-regulated protein kinases (ERK) without the involvement of angiotensin II (Ang II) in cardiomyocytes. We examined the effects of mechanical strain on ERK phosphorylation levels in the absence of Ang II using rat mesangial cells. The ratio of phosphorylated ERK (p-ERK) to total ERK expression was increased by cyclic mechanical strain in a time- and elongation strength-dependent manner. With olmesartan [Ang II type 1 receptor (AT1R) antagonist] pretreatment, p-ERK plateau levels decreased in a dose-dependent manner (EC(50) = 1.3 x 10(-8) M, maximal inhibition 50.6 +/- 11.0% at 10(-5) M); a similar effect was observed with RNA interference against Ang II type 1A receptor (AT(1A)R) and Tempol, a superoxide dismutase mimetic. In addition to the inhibition of p-ERK levels, olmesartan blocked the increase in cell surface and phosphorylated p47(phox) induced by mechanical strain and also lowered the mRNA expression levels of NADPH oxidase subunits. These results demonstrate that mechanical strain stimulates AT1R to phosphorylate ERK in mesangial cells in the absence of Ang II. This mechanotransduction mechanism is involved in the oxidative stress caused by NADPH oxidase and is blocked by olmesartan. The inverse agonistic activity of this AT1R blocker may be useful for the prevention of mesangial proliferation and renal damage caused by mechanical strain/oxidative stress regardless of circulating or tissue Ang II levels.
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Yatabe et al. (2009) studied this question. Olmesartan was evaluated on p-ERK plateau levels (maximal inhibition 50.6 +/- 11.0%). Olmesartan pretreatment dose-dependently decreased mechanical strain-induced p-ERK plateau levels in rat mesangial cells (maximal inhibition 50.6 +/- 11.0% at 10^-5 M).
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